The overarching goal of this project is to describe the long-term consequences of fetal/neonatal glucocorticoid exposure on the developing hypothalamo-pituitary-adrenal (HPA) axis. It has been shown that fetal and neonatal insults can affect the developing HPA axis, resulting in stress hyper-reactivity in adulthood. Females are more susceptible to these effects than males. Early exposure of the developing brain to glucocorticoids is responsible for these long lasting changes in HPA function, yet the cellular mechanisms responsible for programming the memory of early glucocorticoid exposure to adult stress responsiveness remains unknown. Such observations have implication in the study of major depressive disorder (MOD). Clinical and preclinical studies show a causal link between the dysregulation of the HPA axis and behavioral pathology. Furthermore, depression is prevalent in females with F:M ratios of greater than 2:1. Clinical studies of depressed patients show gender differences that arise at adolescence as reflected by an increased incidence of MDD in girls and decreased incidence in boys. Preliminary data presented in this application show that the HPA axis of rodents is sexually differentiated and, if extrapolated to humans, such a sex difference may underlie the sex differences in the prevalence of MDD. Perinatal exposure to glucocorticoids can increase the number of dying cells within the lateral PVN, in female but not male neonates and increase expression of some pro-apoptotic genes in the neonatal brain. This raises the possibility that perinatal exposure to glucocorticoids can permanently change the function of the adult HPA axis by altering the numbers of some neurons within or around the PVN. Alternatively, long term changes in gene expression may be due to altered DMA methylation as a result of neonatal glucocorticoid or gonadal steroid hormone. Studies in this application will test two hypotheses regarding the fetal programming of adult stress responsiveness 1) That prenatal/neonatal exposure to stress causes permanent changes in the function of the HPA axis by either increasing the incidence of death in a select neuronal phenotype in the PVN, or by causing permanent changes in gene expression in PVN neurons through DNA methylation. 2) That there are sex-specific affects of fetal/neonatal glucocorticoid exposure on the developing PVN as a result of molecular interactions between GR and ER.